Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Autor: Christine L. Mummery, Olaf van Tellingen, Hermen S. Overkleeft, Charlotte L. Zuur, Jacques Neefjes, Dennis P A Wander, Jeroen Bakker, Xiaohang Qiao, Tessa van Herwaarden, Elisa Giacomelli, Anke M. Smits, Baoxu Pang, Milena Bellin, Valeria V. Orlova, Jimmy J. Akkermans, Sophie Gerhardt, Linda Smit, J.-Y. Song, Sabina Y van der Zanden, Noortje van Gils, Ramon Arens, Junmin Li, Arjo Rutten, Daniel M. Borràs, Suzanne van Duikeren, Xiao Yang Li, Leon G.J. Tertoolen
Přispěvatelé: Hematology laboratory, CCA - Cancer biology and immunology
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Qiao, X, van der Zanden, S Y, Wander, D P A, Borràs, D M, Song, J Y, Li, X, van Duikeren, S, van Gils, N, Rutten, A, van Herwaarden, T, van Tellingen, O, Giacomelli, E, Bellin, M, Orlova, V, Tertoolen, L G J, Gerhardt, S, Akkermans, J J, Bakker, J M, Zuur, C L, Pang, B, Smits, A M, Mummery, C L, Smit, L, Arens, R, Li, J, Overkleeft, H S & Neefjes, J 2020, ' Uncoupling DNA damage from chromatin damage to detoxify doxorubicin ', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 26, pp. 15182-15192 . https://doi.org/10.1073/pnas.1922072117
Proceedings of the National Academy of Sciences, 117(26), 15182-15192. NATL ACAD SCIENCES
Proceedings of the National Academy of Sciences of the United States of America, 117(26), 15182-15192. National Academy of Sciences
Proceedings of the National Academy of Sciences of the United States of America, 117(26), 15182-15192
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Popis: Significance Anthracyclines like doxorubicin are anticancer drugs, used by over 1 million cancer patients annually. However, they cause severe side effects, most notably, cardiotoxicity and therapy-related malignancies. It is unclear whether these side effects are directly linked to their anticancer activity. Doxorubicin exerts two activities: DNA damage and chromatin damage. Here, we show that both activities conspire in the cardiotoxicity, while doxorubicin variants with only chromatin-damaging activity remain active anticancer drugs devoid of side effects. This challenges the concept that doxorubicin works primarily by inducing DNA double-strand breaks and reveals another major anticancer activity, chromatin damage. Translating these observations will yield anticancer drugs for patients that are currently excluded from doxorubicin treatment and improve the quality of life of cancer survivors.
The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
Databáze: OpenAIRE
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